Mucus plugs form in the airway lumens of CF and COPD patients, raising the likelihood that ion transport and mucin secretion have become uncoupled. We have previously shown that the height (volume) of normal (NL) airway surface liquid (ASL) is regulated, and that dysregulation of CF airway ion transport due to a lack of CFTR causes ASL volume depletion and cessation of mucus transport. This defect is predicted to impair the mucus component of the innate host defense, leading to increased frequency of respiratory infections. The underlying mechanisms of ASL regulation and the relevance to CF and COPD are unknown. Our long term goal is to understand how ASL volume is autoregulated in normal as compared to diseased (CF and COPD) airways under physiological conditions, and in response to acute challenges such as cigarette smoke, inflammation and respiratory viral infections. We have previously observed that extracellular purine nucleoside (adenosine)-dependent pathways for ASL volume autoregulation are present in normal but not CF airways. However, when cultured with a novel system that mimics the shear stresses associated with normal tidal breathing in vivo, CF cultures exhibit ASL volume homeostasis and maintain mucus transport mediated by shear stress-dependent extracellular purine nucleotide (ATP) release. Superimposed on the acute regulation of ASL volume by ATP and ADO are chronic effects of cytokines/inflammatory mediators through regulation of ion channel density and signaling pathways. CF airways are uniquely vulnerable to viral (RSV) infections deplete ASL volume via upregulation of extracellular ATPases causing reduction of ASL ATP levels. Cigarette smoke exposure also inhibits CFTR and ADO-regulated ASL volume regulation. Based on these observations, we propose that an initiating event in the development of COPD and CF is a failure of ion transport to regulate ASL volume, resulting in the accumulation of poorly cleared mucus plaques/plugs on airway surfaces. These plaques/plugs then act as the primary site of pathogen infections, impair macrophage/neutrophil influx and ultimately lead to the airway remodeling that is characteristic of CF airway disease and COPD. Elucidation of the basic mechanisms that account for the major inherited (CF) and acquired (COPD) forms of chronic inflammatory airways disease is vital for the public health of the US population. Such knowledge will likely lead to the development of novel, uniquely effective therapies for these diseases.